Steroid compounds having contraceptive and anti-osteoporosis activity

ABSTRACT

The invention relates to a steroid compound having the formula (I)                    
     comprising a ring E, said ring sharing carbon atoms at position 16 and 17 with the five-membered ring D and being α with respect to said D-ring. In addition, the carbon atom at position 17 is substituted with an oxygen atom-comprising group through a CO bond. The invention also relates to a pharmaceutical composition comprising said steroid compound. The steroid compounds of the present invention are very suitable for use in the prevention or treatment of peri-menopausal or menopausal complaints, more preferably the prevention or treatment of osteoporosis. Furthermore, the steroid compounds of the present invention can be used for contraceptive purposes.

This application is a continuation of U.S. Ser. No. 09/026,348, filedFeb. 19, 1998, now U.S. Pat. No. 6,077,873.

FIELD OF THE INVENTION

The present invention relates to a new class of steroid compounds, andin particular to a steroid compound having the formula (I)

wherein:

R₃ is ═O; —OH; ═NOR; —OR or —OOCR, in which R is an alkyl group having 1to 6 carbon atoms;

R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or 2 wherein the steroidcompound optionally may have one or more double bonds chosen from thegroup of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of the rings Aor B may be aromatic; The presence or absence of hydrogen atoms thathave not been depicted, depends on whether a given ring is saturated,unsaturated, or aromatic, and is immediately evident to the normallyskilled person.

R₇ is H; C₁₋₄-alkyl; C₂₋₅ alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group of fluorine and chlorine atoms;

R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl or C₁₋₄-alkylidene,wherein the alkyl, alkenyl; alkynyl or alkylidene group may besubstituted with 1 to 3 halogen atoms independently selected from thegroup of fluorine and chlorine atoms;

E represents, including carbon atoms 16 and 17 of ring D, a four toseven-membered ring, said ring being a with respect to the D-ring,substituted with R_(E) and optionally comprising one or two endocyclicdouble bonds; The α-position of ring E vis-à-vis ring D is essential, asthe corresponding steroids having a ring E in the β-position do notpossess the required biological activity. It should be noted that, forreasons of nomenclature, some compounds according to the invention havea name which includes a reference to 16β and/or 17β substituents.However, irrespective thereof, in all compounds of the invention, theE-ring as a whole is α.

R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-annulated cycloalkyl; —OR; —SR; —OOCR; —NHR; —NRR; —NHCOR,wherein R (and in the case of R_(E) being —NRR each R independently ofthe other) is an alkyl with 1 to 6 carbon atoms; —NCO; —(CH₂)_(n)—N₃ or—(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl, alkenyl, alkynyl,alkylidene or cycloalkyl group may be substituted with 1 to 3substituents independently selected from the group consisting of —OR;—SR; —OOCR; —NHR; —NRR; and —NHCOR, with R being defined as above,fluorine atoms and chlorine atoms;

R₁₇ is —OH; —OCH₂OR; —OR or —OOCR wherein R is an alkyl with 1 to 6carbon atoms;

Any alkyl alkenyl, alkynyl and alkylidene groups in the steroid compoundhaving the formula (I) may be branched or unbranched. If R₃, R₆ or R₁₁is connected to the steroid skeleton through a single bond, thesubstituted carbon atom of the steroid skeleton either comprises ahydrogen atom or is involved in a double carbon-carbon bond. R_(E) isconnected to the E-ring through a single bond, the substituted carbonatom of the E-ring also comprises a hydrogen atom.

It was surprisingly found that the steroid compounds of the presentinvention have excellent and interesting estrogenic and/or progestagenicproperties. Due to these specific characteristics, the steroid compoundsof the present invention are very suitable for use in the prevention ortreatment of peri-menopausal or post-menopausal complaints, includingclimacteric symptoms such as hot flushes and mood disturbances,urogenital complaints such as incontinence, skin (and vagina epithelium)atrophy, and other symptoms associated with estrogen-deficiency orestrogen withdrawal, such as osteoporosis, atherosclerosis, andAlzheimer's disease. The steroid compounds according to the inventionare very suitable for the prevention or treatment of osteoporosisresulting from estrogen-deficiency.

Furthermore, the steroid compounds of the present invention can be usedfor contraceptive purposes.

BACKGROUND OF THE INVENTION

Steroid compounds having a 16, 17-ring substitution have been described.Chemical Abstracts 89: 215660p (Kamernitskii A V. et al.) describes asteroid compound comprising a 16,17 anellated 5- or 6-membered ring andan acetyl group at position 17. The compounds disclosed in thispublication however differ from the steroid compounds according to thepresent invention in that the carbon atom at position 11 carries ahydrogen atom.

Chemical Abstracts 123: 285604t (Wang, J. et al.) discloses steroidcompounds having a 10-membered E-ring with two triple bonds, a hydroxylgroup at position 17, and a hydrogen atom at position 11.

EP 411.733 (Schering AG) discloses a steroid compound having a6-membered E-ring, the carbon atom at position 17 being involved in aCO-bond. The compounds disclosed in EP 411733 however differ from thesteroid compounds according to the present invention in that the carbonatom at position 11 carries a (substituted) aryl group. These compoundsare disclosed to be competitive antagonists for progesterone.

SUMMARY OF THE INVENTION

Thus, none of this prior art references disclose the steroid compoundsaccording to the present invention. The steroid compounds according tothe present invention differ from those disclosed in the state of theart by the substitution at position 11, 16, and 17. More in particular,the steroid compounds according to the invention comprise a ring E,sharing carbon atoms at position 16 and 17 with the five-membered ring Dand being α with respect to said D-ring. In addition, the carbon atom atposition 17 is substituted with an oxygen atom-comprising group througha CO bond. The carbon atom at position 11 does not carry an aryl group.

Furthermore, none of the above publications suggests the interestingpharmaceutical properties of the steroid compound according to thepresent invention. Hence, the steroid compounds according to the presentinvention form a novel class of steroid compounds, as defined by theirin vitro and in vivo activity.

Specifically for obtaining selective estrogen activities, in the steroidcompounds according to the invention, the E-ring suitably is afive-membered ring. It is preferred that the E-ring is a six-memberedring, in view of the compounds' favourable estrogen/progestogenprofiles, which include both potent, selective estrogens, and potentmixed estrogen/progestagen compounds. According to a preferredembodiment, the A-ring is aromatic and the remaining rings aresaturated, wherein it is further preferred that R₇ is α-propyl. The mostpreferred compound, coded Org 38515, is further characterized in that R₃and R₁₇ are OH, and R₆, R₁₁, and R_(E) are H.

The present invention also relates to a pharmaceutical compositioncomprising the steroid compound according to the invention mixed with apharmaceutically acceptable auxiliary, such as described in the standardreference, Gennaro et al., Remmington's Pharmaceutical Sciences, (18thed., Mack publishing Company, 1990, see especially Part 8:Pharmaceutical Preparations and Their Manufacture.). The mixture of thesteroid compounds according to the invention and the pharmaceuticallyacceptable auxiliary may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules or suppositories. By meansof pharmaceutically suitable liquids the compounds can also be appliedas an injection preparation in the form of a solution, suspension,emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g.tablets, the use of conventional additives such as fillers, colorants.polymeric binders and the like is contemplated. In general anypharmaceutically acceptable additive which does not interfere with thefunction of the active compounds can be used. The steroid compounds ofthe invention may also be included in an implant, a vaginal ring, apatch, a gel, and any other preparation for sustained release.

Suitable carriers with which the compositions can be administeredinclude lactose, starch, cellulose derivatives and the like, or mixturesthereof used in suitable amounts.

Furthermore, the invention relates to the use of the steroid compoundaccording to the invention for the manufacture of a medicament having aperi- and/or post-menopausal complaints relieving activity, inparticular an anti-osteoporosis activity. Thus the invention alsopertains to the medical indications of peri- and/or post-menopausal(climacteric) complaints and osteoporosis, i.e. a method of treatment inthe field of HRT (hormone replacement therapy), comprising theadministration to a patient, being a woman, of a compound as describedhereinbefore (in a suitable pharmaceutical dosage form).

Further, the invention relates to the use of the steroid compoundaccording to the invention for the manufacture of a medicament havingcontraceptive activity. Thus the invention also pertains to the medicalindication of contraception, i.e. a method of contraception comprisingthe administration to a subject, being a woman or a female animal, of acompound as described hereinbefore (in a suitable pharmaceutical dosageform).

Finally the invention relates to the use of the steroid compound for themanufacture of a medicament having selective estrogenic activity, such amedicament being generally suitable in the area of HRT (hormonereplacement therapy).

DETAILED DESCRIPTION OF THE INVENTION

The synthesis of the 16α,17α-anellated steroids is accomplishedgenerally by first attaching a suitably functionalized C3 or C4 fragmentto the C₁₆ α-position of the steroid (for formation of 5-membered or6-membered rings respectively). To facilitate this process the 17-ketofunction is generally converted first into a dimethylhydrazone, which iscleaved off again after assembly of the required side chainfunctionality's. Ring closure can be brought about by organometallictechniques, such as the treatment of ω-iodoalkyl derivatives withtransition metals like samarium (in the case of 5-membered rings,exemplified in example I), or by the formation of organolithiumderivatives by use of reagents like t-butyllithium (exemplified for theformation of 6-membered rings in example II). Alternatively theformation of five membered rings can be brought about via generation ofanions by fluoride assisted cleavage of silicon groups in ω-silyl sidechains, as found in example III.

ω-Acetylenes can serve similarly well as substrates for ring closurereactions in radical anion mediated reactions, using elements likesodium or lithium as exemplified example IV.

An entirely different approach consists in formation of anellated ringsby applying olefin metathesis techniques, using catalysts derived fromtransition metals like ruthenium, molybdenum or tungsten. To this end16α, 17α dialkenylated steroids serve as substrates. They are easilyavailable by alkylation of steroidal ketones at C-16, followed byintroduction of an alkene fragment via organometallic anionicderivatives (lithiates etc.). As an example of such a reaction theformation of both 5- and 6-membered rings has been demonstrated inexample V.

Thus, in addition to the above compounds of the invention and thevarious uses of these compounds, the invention also provides the abovemethods of making 16,17 anellated steroids by generating a ring added toa steroid skeleton, which ring includes carbon atoms 16 and 17 of saidskeleton. These methods, which have not been applied in the art ofsteroid chemistry, allow making a broad range of 16,17 anellatedsteroids. E.g. in DE 19709870 (not pre-published) a method is describedwhich has serious restrictions in respect of the specific compounds thatcan be synthesized. The method involves a [4+2] cycloaddition reactionof butadiene or dimethylbutadiene with a strongly activated double bondat C₁₆₋₁₇. This means that at C₁₇ always a strong electron-withdrawingsubstituent, such as —CN or -acyl, must be present, which seriouslylimits the number of options. Further, the method allows only 6-rings tobe made, allows a limited number and variety of compounds, and requiresa symmetric butadiene structure, as the methods lacks regioselectivity.The methods of the invention do not have these restrictions, and allowfor the stereoselective and regioselective synthesis of a wide varietyof 5- and 6-ring 16,17 anellated steroids as described hereinbefore.These methods thus make for an inventive contribution to the field ofsteroid chemistry.

The present invention will be illustrated by the following Figures andExamples without necessarily being restricted to the specificembodiments disclosed therein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: schematic representation (2-13) of a process for the synthesisof two steroid compounds (12 and 13) according to the present inventionas described in Example I.

FIG. 2: schematic representation (14-21) of a process for the synthesisof three steroid compounds (19, 20, and 21) according to the presentinvention as described in Example II.

FIG. 3: schematic representation of a process (22-33) for the synthesisof two steroid compounds (30 and 33) according to the present inventionas described in Example III.

FIG. 4: schematic representation of a process (34-39) for the synthesisof a steroid compound (39) according to the present invention asdescribed in Example IV.

FIG. 5: schematic representation of a process (40-44) for the synthesisof a steroid compound (44) according to the present invention asdescribed in Example V.

FIG. 6: schematic representation of a process (40-47) for the synthesisof a steroid compound (47) according to the present invention asdescribed in Example VI.

The numbers between parentheses refer to the corresponding structuralformula of compounds represented in the scheme.

EXAMPLE I

Although the required substrate 1 may be easily synthesized bydehydrogenation of steroids at C6C7 according to literature methods(e.g. by use of chloranil or DDQ) a new method was developed whichallows a variety of 17-α-ethinyl, 17-β-hydroxy steroids to be used aswell as substrates for gaining access to appropriate 17-keto steroids.They can be de-ethinylated by treatment with copper carbonateprecipitated on Celite. Though a similar conversion has been describedin literature using silver carbonate, the presently described method hasthe advantage of using a far more cheaper reagent. A batch of CuCO₃ onCelite was prepared as follows. A 100 gr of Celite was purified bystirring in a mixture of 500 ml of methanol and 100 ml of 6N HCl for 15min. The mixture was filtered and washed several times with water untilneutral. The material thus obtained was slurried into a solution of 60 gof Cu(NO₃)₂.3H₂O in 400 ml of water. To this was then added dropwisewith efficient stirring a solution of 30 g of Na₂CO₃.H₂O in 200 ml ofwater. After stirring for an additional 15 min. the material wasfiltered and washed with water (In order to remove most of the waterprior to drying, the material was slurried in acetone and filtered andsubsequently washed with pentane) Drying was finally performed in vacuoat 80° overnight, to yield 160 g of reagent.

4 G of (17β)-17-hydroxypregna-4,6-dien-20-yn-3-one and 20 gr. ofCuCO₃-Celite were suspended in 100 ml of toluene. The mixture wasrefluxed for about 6 hr with a Dean-Stark trap to remove some residualwater. The progress of the reaction was monitored by tlc. Aftercompletion of the reaction the reaction mixture was filtered overCelite. The filtrate was concentrated and the residue treated withisopropylether-hexane to provide 2.4 g ofpregna-4,6-dien-20-yn-3,17-dione, m.p. 182-184. Reduction of this withsodiumborohydride provided the required 17β alcohol, which uponacetylation with acetic anhydride provided the required substrate 1.

(7-alpha,17 beta)-17-(acetyloxy)-7-propylestr-4-en-3-one (2)

A solution of propyl lithium (prepared from 1.4 g of Li and 9 ml ofpropyl bromide in 60 ml of ether at −20 C) was added at −40 C to 7.6 gof CuI in 60 ml of dry THF.

After stirring for an additional 0.5 hr , a solution of 5.2 g of (17beta)-17-(acetyloxy)estra-4,6-dien-3-one (1) in 20 ml of THF was addeddropwise at −40 C. Upon stirring for an additional 15 minutes thereaction was complete, and the mixture was poured onto 300 ml ofsaturated NH₄Cl solution, followed by extraction with ethyl acetate. Theorganic material, isolated after washing, drying and evaporation of thesolvent, was taken up in 30 ml of THF and stirred in the presence of 3ml of 6N H₂SO₄ to isomerize some Δ5,6 isomer to Δ4,5 isomer. After 1 hrthe mixture was neutralized with saturated NaHCO₃ solution and extractedwith ethyl acetate. Chromatography of the crude product over silica gel(heptane/ethyl acetate 8/2) provided 2.1 g of 2, m.p. 97-100° C.

(7-alpha,17-beta)-7-propoylestra-1,3,5(10)-triene-3,17-diol 17-acetate(3)

To a solution of 15 g of 2 in 300 ml of acetoFitrile was added 12 g ofCuBr₂. The mixture was stirred for 20 hr, while monitoring the reactionby TLC (tlc plates were purchased from Merck A.G., Germany). Thereaction was then poured onto water and extracted with ethyl acetate.Chromatography of the crude product over a short silica gel column(heptaine/ethyl acetate 4/1 as eluent) provided 13.5 g of 3 as whiteamorphous material. R_(f) 0.57 (hept/ethylac. 7/3).

(7-alpha, 17 beta)-3-methoxy-7-propylestra-1,3,5(10)-trien-17-ol acetate(4)

To a solution of 13.5 g of 3 in 60 ml of DMF was added 2.4 g of NaH (60%dispersion in mineral oil) in portions. After stirring for 1 hr hydrogenevolution had subsided. Then 3 ml of methyl iodide was added dropwise.After one hour stirring at ambient temperature, the reaction mixture waspoured into 300 ml of water, and the product was extracted with ethylacetate. The residue which remained after evaporation of the volatileswas taken up in 20 ml of THF and a solution of 4 g of NaOH in 80 ml ofCH₃OH was introduced. After stirring for 1 hr the saponification wascomplete. The reaction mixture was neutralized by addition of 1N H₂SO₄,and the product was extracted into ethyl acetate, to provide 11.5 g of4, R_(f) 0.34 (hept./ethylac. 7/3).

(7-alpha)-3-methoxy-7-propylestra-1,3,5(1)-trien-17-one (5)

To a solution of 10.4 g of 3-O-methyl, 7α-propylestradiol 4 in 50 ml ofmethylene chloride were subsequently added 15 g. of powdered sodiumacetate, 30 g of silicagel and 32 g of pyridinium chlorochromate. Afterstirring for 1 hr the oxidation was complete. Excess reagent wasdestroyed by addition of 1 ml of isopropanol, followed by 150 ml ofhexane 10 min. later. All the precipitates were filtered over Celite,and the filtrate was concentrated to dryness. This provided 9.6 g ofessentially pure ketone 5; R_(f) 0.54 (hept./ethyl acetate 7/3).

(7-alpha)-3-methoxy-7-propylestra-1,3,5(10)-trien-17-onedimethylhydrazone (6)

To a solution of 11.2 g. of 7α-propyl-3-O-methylestrone 5 in 60 ml oftoluene were added 6 ml of dimethylhydrazine and 0.5 ml. oftrifluoroacetic acid.

The mixture was refluxed for 1.5 hr. After cooling to r.t. the reactionmixture was neutralized with 5% NaHCO₃ and the organic layer was washedseveral times with water and dried over sodium sulfate. Afterconcentration and chromatography 11.4 g of the hydrazone 6 remained asan oil; R_(f) 030 (hept/ethylac. 7/3).

[7-alpha,16-alpha(S)]-16-[3[[dimethyl(1,1-dimethylethyl)silyl]oxy]-2-methylpropyl]-3-methoxy-7-propylestr-1,3,5(10)-trien-17-onedimethylhydrazone (7)

To a solution of 2.6 g of 6 in 30 ml of dry THF was added at −40° C. 5.6ml of BuLi (1. 5 N solution in hexane). After stirring for 0.5 hr atthis temperature 2.7 g of(2R)-2-methyl-3-iodopropanol-O-tert.butyldimethylsilyl (TBDMS) ether in5 ml. of THF was introduced. After stirring for an additional hr at −20°C. the reaction mixture was poured into water and extracted. Subsequentchromatography provided 4.6 g of 7; R_(f) 0.50 (hept./ethylac. 7/30.50).

[7-alpha,16alpha(S)]-16-(3-hydroxy-2-methylpropyl)-3-methoxy-7-propylestra-1,3,5(10)trien-17-onedimethylhydrazone (8)

A solution of 4.6 g of 7 in 5 ml of THF was treated with 15 ml of 1MTBAF in THF for 1 hr at 50° C. The mixture was diluted with 100 ml ofwater and extracted with ethyl acetate. After passing the productthrough a short silicagel column 3.1 g of 8 was obtained as an oil;R_(f) 0.18 (hept./ethylac. 7/3).

[7-alpha,16-alpha(S)]-16-[2-methyl-3-[[(4-methylphenyl)sulfonyl]oxy]propyl]-7-propylestra-1,3,5(10)-trien-17-one(10)

A solution of 2.8 g of 9 in 7 ml of pyridine was treated at 0° C. with2.6 g of tosyl chloride. After stirring for 2 hr. excess reagent wasdecomposed by stirring with ice for 0.5 hr. The product was extracted byethylacetate and purified by chromatography, to provide 3.2 g of 10 as acolorless oil; R_(f) 0.35 (hept./ethylac. 7/3).

[7-alpha,16-alpha(S)]-16-(3-hydroxy-2-methylpropyl)-3-methoxy-7-propylestra-1,3,5(10)trien-17-one(9)

A mixture of 3.1 g of 8 in 30 ml. of acetone and 3 ml of water wastreated with 3 g of amberlyst-15 acidic resin(Fluka AG.) for 2 hr at 55°C. Thereafter the reaction mixture was filtered and concentrated, toprovide 2.8 g of 9 as an oil; R_(f) 0.75 (heptane/acetone 1/1).

[7-alpha-16-alpha,(S)]-16-(3-iodo-2-methylpropyl)-7-propylestra-1,3,5(10)-trien-17-one(11)

A mixture of 3.2 g of 10 and 10 g of sodium iodide in 30 ml of acetonewas heated at 65° C. for 1 hr. After pouring the reaction into water andextraction with ethyl acetate 2.9 g of iodide 11 were obtained; R_(f)0.55 (hept./ethylac. 7/3).

(4′S,7-alpha,16beta,17-beta)-3,4′,5′,16-tetrahydro-3-methoxy-4′-methyl-7-propyl-17H-cyclopenta[16,17]estra-1,3,5(10)-trien-17-ol(12)

A solution of SmI₂ was prepared from 3 g of samarium metal and 4.7 g of1,2-diiodoethane in 70 ml of dry THE. To this solution was added at 0°C. 20 mg of tris(dibenzoylmethanato)iron, followed by a solution of 2.8g of 11 in 10 ml of THF. After stirring for an additional hr the mixturewas poured onto water, acidified with 2N H₂SO₄ and extracted with ether.

The crude product thus obtained was chromatographed to remove some16,17-beta isomer, and provided 1.6 g of 12; R_(f) 0.32 (hept/ethylac.7/3).

The related beta isomer has a R_(f) value of 0.37.

(4′S,7-alpha,16-beta,17-beta)-3′,4′,5′,16-tetrahydro-4′-methyl-7-propyl-17H-cyclopenta[16,17]estra-1,3,5(10)-trien-3,17-diol(13)

To a solution of 700 mg of 12 in 5 ml of toluene was added 15 ml ofDIBAL (1M in toluene). The mixture was refluxed for 3 hr to effect ethercleavage. Excess reagent was destroyed by the addition of water,followed by further dilution with 40 ml of 2N HCl. The product wasextracted with ethylacetate. After drying and concentration, the residuewas triturated with diisopropyl ether, to provide 460 mg of crystalline13; M.p. 166-168° C. R_(f) 0.36 (hept./ethylac. 7/3).

EXAMPLE II

(7-alpha,16-alpha)-16-[4-[[dimethyl(1,1-dimethylethyl)silyl]oxy]butyl]-3-methoxy-7-propylestra-1,3,5(10)-trien-17-onedimethylhydrazone (14)

To a solution of 3.9 g of the hydrazone 6 in 45 ml of dry THF was addedat −60° C. 8.5 ml of 1.5N BuLi solution in hexane. After stirring for0.5 hr a solution of 4.2 g of 4-iodobutanol-TBDMS ether in 5 ml of THFwas added dropwise. The mixture was subsequently stirred at −20 for 1 hrand then poured into 200 ml of water and extracted with ethyl acetate.

Chromatographic purification over silica gel provided 6.2 g of 14 as anoil; R_(f) 0.52 (hept./ethylac. 7/3).

(7-alpha,16-alpha)-16-(4-hydroxybutyl)-3-methoxy-7-propylestra-1,3,5(10)-trien-17-onedimethylhydrazone (15)

A solution of 6 g of 14 in 5 ml of THF was treated with 20 ml of 1Mtetrabutylammonium fluoride in THF for 2 hr. The reaction was pouredinto water and extracted with ethyl acetate. After chromatography 4.1 gof 15 remained as an oil; R_(f) 0.17 (hept./ethylace. 7/3).

(7-alpha,16-alpha)-16-(4-hydroxbutyl)-3-methoxy-7-propylestra-1,3,5(10)-trien-17-one(16)

A mixture consisting of 4 g of 15, 40 ml of acetone, 4 ml of water and 4g of Amberlyst-15 acid resin was stirred for 2 hr at 50° C. The mixturewas filtered, concentrated, taken up in 40 ml of toluene, dried andconcentrated, to provide 3.7 g of essentially pure 16; R_(f) 0.61(hept/acetone 1/1); starting material R_(f) 0.65.

(7-alpha,16-alpha-16-[4-[[(4-methylphenyl)sulfonyl]oxy]butyl]-7-propylestra-1,3,5(10)trien-17-one(17)

A mixture of 3.7 g of 16 and 3.2 g of tosylchloride in 10 ml of drypyridine was stirred at 0-5° C. for 3 hr. After dilution with water theproduct was extracted with ethyl acetate. Chromatographic purificationprovided 4.6 g of tosylate 17; R_(f) 0.45 (hept./ethylac. 7/3) 0.45.

(7-alpha,17-alpha)-16-(4-iodobutyl)-3-methoxn-7-propylestra-1,3,5(10)-trien-17-one(18)

A mixture of 4.6 g of 17 and 20 g of sodium iodide in 50 ml of acetonewas heated at 60° for 1.5 hr. The reaction mixture was concentrated,diluted with water and extracted with toluene. After drying andconcentration 4.4 g of iodide 18 remained as essentially pure material;R_(f) 0.50 (hept./ethylac. 7/3).

(7-alpha. 16-alpha,17-alpha)-3-methoxy-7-propyl-16,24-cyclo-19,21-dinorchola-1,3,5(10)trien-17-ol(19)

A solution of 3.8 g of the iodide 18 in 20ml of dry THF was treated at3-60° C. with 9 ml of a 1.7M solution of tertbutyllithium in heptane.After stirring for an additional 15 min. at −60° C., the mixture waspoured into water and extracted with ethyl acetate. The crude productobtained after removal of the volatiles was triturated with heptane, toprovide 1.9 g of essentially pure 19; M.p. 161-162° C. R_(f) 0.40(hept./ethylac. 7/3).

(7-alpha,16-alpha,17-alpha)-17-hydroxy-7-propyl-16,24-cyclo-19,21-dinorchol-4-en-3-one(21)

To a solution of 1 g of lithium in 90 ml of liquid ammonia was added at−33° C. a solution of 1.3 g of 19 in 30 ml of dry THF. After stirring inrefluxing ammonia for an additional 4 hr, the reaction was treated with20 ml of ethanol followed by evaporation of the ammonia under a steadystream of nitrogen. The residue was diluted with 50 ml of water andextracted with ethylacetate. Concentration of the organic phase,followed by trituration of the residue with heptane, provided 1.1 g ofpure dienolether intermediate; M.p. 190-192° C.

This material was dissolved in 25 ml of THF and treated with 5 ml of 6NH₂SO₄. After stirring for 6 hr the mixture was neutralized with Na₂CO₃and the product extracted with ethyl acetate. Chromatographicpurification of the crude material thus obtained gave 610 mg of 21 as awhite foam; R_(f) 0.25 (hept/ethylac. 7/3).

(7-alpha,16-alpha,17-alpha)-7-propyl-16,24-cyclo-19,21-dinorchola-1,3,5(10)-trien-3,17-diol(20)

To a solution of 600 mg of 19 in 5 ml of dry toluene was added 12 ml of1M DIBAH (diisobutylaluminum hydride) in toluene. After 2 hr ofrefluxing the demethylation was complete; excess reagent was destroyedby careful addition of water and subsequently the mixture was pouredonto 50 ml of 4N hydrochloric acid, and the product extracted into ethylacetate. The organic layer was dried, concentrated and the residuetreated with diisopropylether, to provide 310 mg of 20; M.p. 240° C.,R_(f) 0.20 (hept./ethylac. 7/3)

EXAMPLE III

(11-beta,16-alpha)-11-methyl-16-[2-[(trimethylsilylmethyl]prop-2-enyl]estr-5-ene-3,17-dione3-cyclic(1,2-ethanediyl)acetal (23)

To a solution of 12.7 ml of hexamethyldisilazane in 50 ml of THF wasadded at −50° C. 40 ml of 1.5M BuLi in heptane solution. After stirringfor 20 min. a solution of 16.5 g of 22 in 100 ml of THF was run inslowly at −50° C. After stirring for an additional 0.5 hr a solution of25 g of 3-iodo-2-trimethylsilylmethylpropene in 25 ml of THF wasintroduced. The reaction mixture was stirred at −20° C. for anadditional 3 hr, and then poured onto 400 ml of water. The product wasextracted with ethyl acetate and chromatographed over silicagel. Aftertrituration with heptane 12.5 g of product 23 was obtained; M.p.184-185° C.; R_(f) 0.55 (hept./ethylac. 7/3).

(11-beta,16-beta,17-beta)-4′,5′,16,17-tetrahydro-17-hydroxy-11-methyl-4′-methylene-3′H-cyclopenta[16,17]estra-5,16-dien-3-one3-cyclic (1,2-ethanediyl acetal) (24)

A solution of 8.8 g of 23 in 200 ml of dry THF was treated with 4 ml of1M tetrabutylammonium fluoride (TBAF) in THF. The mixture was refluxedfor 15 min. to complete the ring closure reaction. An additional amountof 15 ml of 1M TBAF solution was then added and refluxing prolonged for1 hr in order to cleave 17-O-silyl ether formed during the reaction. Themixture was subsequently concentrated to a small volume and diluted withwater, followed by extraction with ethylacetate. Chromatographicpurification provided 4.0 g of 24; M.p. 141-142° C., R_(f) 0.28(hept./ethylac. 7/3).

(4′S,11-beta,16-beta,17-beta)-4′,5′,16,17-tetrahydro-17-hydroxy-4′-(hydroxymethyl)-11-methyl-3′H-cyclopenta[16,17]estra-5,16-dien-3-one3-cyclic (1,2-ethanediyl acetal) (25), and its 4′R analog (26).

A solution of borabicyclononane (9-BBN) was prepared from 3 ml of 10Mboranedimethylsulfide complex and 4 ml of 1,5-cyclooctadiene in 30 ml ofdry THF. To this was added a solution of 3.8 g of 24 in 10 ml of THF.

The mixture was stirred for 2 hr and then excess reagent was destroyedby careful addition of 1 ml of ethanol, followed by 20 ml of 2N NaOHsolution and 10 ml of 30%-H₂O₂. This mixture was stirred for another 3hr and then further diluted with water and extracted with ethylacetate.

The crude product was chromatographed over silicagel (toluene/acetone aseluent) to provide 2.1 g of 25 (M.p. 178° C., R_(f) 0.47 (tol./acet.1/1)) and 1.2 g of 26 (R_(f) 0.55 (tol./acet. 1/1)).

(4′R,11-beta,16-beta,17-beta)-4′,5′,16,17-tetrahydro-17-hydroxy-11-methyl-4-[[[(4-methylphenyly)sulphonyl]oxy]methyl]-3′H-cyclopenta[16,17]estra-5,16-dien-3-one-3-cyclic(1,2-ethandiyl acetal) (31)

A solution of 1.2 g of 26 and 0.8 g of to syl chloride in 5 ml ofpyridine was stirred at 0-5° C. for 2 hr. Then the mixture was dilutedwith ice-water, stirred for 15 min. and extracted with ethyl acetate.Drying and concentration of the organic phase provided 1.6 g ofessentially pure 31; R_(f) 0.52 (tol./ethylac. 7/3).

(4′R,11-beta,16-beta,17-beta)-4′-butyl-4′,5′,16,17-tetrahydro-17-hydroxy-11-methyl-3′H-cyclopenta[16,17]estra-5,16-dien-3-one(32)

A cuprate reagent was prepared by adding 12 ml of a 2Mpropylmagnesiumbromide/ether solution to 2.3 g of CuI in 20 ml of THF at−20° C. After stirring for 15 min. a solution of 600 mg of 31 in 3 ml ofTHF was added. Stirring was continued for 2 hr more at −20° C. Thereaction was worked up by addition of 60 ml of sat.NH₄Cl and 10 ml of10%-ammonia, followed by extraction with ethyl acetate. The crudeproduct was chromatographed, to provide 420 mg of 32; M.p. 97-98° C.,R_(f) 0.45 (hex./ethylacet. 7/3).

(4′R,11-beta,16-beta-17-beta)-4′-butyl-4′,5′,16,17-tetrahydro-17-hydroxy-11-methyl-3′H-cyclopenta[16,17]estra-4,16-dien-3-one(33)

A solution of 400 mg of 32 in 5 ml of acetone was treated with 2 ml of4N H₂SO₄. After 2 hr at r.t. the mixture was diluted with water andextracted with ethyl acetate. Chromatographic purification afforded 360mg of essentially pure 33 as an amorphous material; R_(f) 0.27(hept./ethylac. 7/3).

(4′S,11-beta,16-beta,17-beta)-4′,5′,16,17-tetrahydro-4′-(hydroxymethyl-11-methyl-17-[(trimethylsilyloxy]-3′H-cyclopenta[16,17]estra-5,16-dien-3-one3-cyclic(1,2-ethanediyl acetal) (27)

The protection of the 17-OH function was performed in a multistepprocedure. First the primary alcohol was acetylated. Thus, to a solutionof 750 mg of 25 in 2 ml of pyridine was added 5 mg of4-dimethylaminopyridine (DMAP), followed by 0.5 ml of acetic anhydride.After stirring for 1 hr. 10 g of ice-water was added, followed byextraction of the product with ethyl acetate. Concentration of theorganic material, and treatment of the residue withheptane-diisopropylether provided 730 mg of monoacetate; M.p. 112° C.This material was dissolved in 3 ml of DMF containing 200 mg ofirnidazole. Then 240 μl of TMS-chloride was added, and the mixture wasstirred for 0.5 hr at room temperature. After addition of 15 ml ofwater, the product was extracted with ether. Upon drying andconcentration 900 mg of essentially pure silylether derivative wasobtained; R_(f) 0.54 (hept./ethylac. 7/3).

This product was dissolved in 3 ml of dry THF and 70 mg of LiAlH₄ wasadded. After stirring for 10 min. the mixture was subsequently treatedwith 0.3 ml of water and 0.1 ml of 2N NaOH and 1 g of NaSO₄. Then it wasfiltered through Celite and concentrated to provide 700 mg of 27 as anamorphous material; R_(f) 0.29 (hept./ethylac. 7/3).

(4′S, 11-beta,16-beta,17-beta)-3,3-[1,2-ethanediylbis(oxy)]-4′,5′,16,17-tetrahydro-11-methyl-17-[(trimethylsilyl)oxy]-3′H-cyclopenta[16,17]estra-5,16-dien-4′-carboxaldehyde(28)

To a solution of 600 mg of 27 in 15 ml of methylene chloride was added1.5 g of anhydrous sodium acetate, 2.5 g of silica gel followed by 2 gof pyridiniumchlorochromate. The mixture was stirred for 1 hr at roomtemperature. Then 50 ml of ether was added and after additional stirringfor 15 min. the reaction was filtered through Celite, followed byevaporation of the volatiles, to provide 420 mg of essentially purecarboxaldehyde 28; a compound slowly solidifying on standing; R_(f) 0.48(hept./ethylac. 7/3).

(4′S,11-beta,16-beta,17-beta)-4′-ethenyl-4′,5′,16,17-tetrahydro-11-methyl-17-[(trimethylsilyl)oxy]3′H-cyclopenta[16,17]estra-5,16-dien-3-one3-cyclic (1,2-ethanediyl acetal) (29)

To 1.3 g of methyltriphenylphosphonium chloride in 25 ml of TMF wasadded 1.7 ml of 1.5M BuLi in hexane solution at −40° C. After stirringfor 30 min. 400 mg of 28 in 2 ml of THF was added. The mixture wasallowed to warm to room temperature in about 0.5 hr and then quenched bypouring into 100 ml of water. The product was extracted with diethylether, and subsequently chromatographed to provide 280 mg of 29 as anoil; R_(f) 0.53 (hept./ethylac. 7/3); starting material R_(f) 0.23.

4′S,11-beta,16-beta,17-beta)-4′-ethenyl-4′,5,′16,17-tetrahydro-11-methyl-17-hydroxy-3′H-cyclopenta[16,17]estra-4,16-dien-3-one(30)

A solution of 260 mg of 29 in a mixture of 3 ml of THF and 3 ml of 4NH₂SO₄ was stirred for 2 hr at 45° C. Then the reaction was neutralizedwith 5% NaHCO₃ solution and the product extracted into ethyl acetate.

Short path silica gel chromatography provided 150 mg of 30; R_(f) 0.25(hept./ethylac. 7/3).

EXAMPLE IV

3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]estra-1,3,5(10)-trien-17-onedimethylhydrazone (35)

To a solution of 15.5 gr. of 3-hydroxyestra-1,3,5(10)-trien-17-onedimethylhydrazone (34) in 200 ml of DMF was added 13 gr. of imidazole,followed by dropwise addition of 15 gr. of TBDMSCl in 20 ml of ether.After stirring for an additional 16 hr the reaction mixture was pouredonto 2 liters of water and the resulting mixture was stirred for anadditional 10 minutes. The precipitate was filtered and dried in vacuo,to provide 20 g of 35, M.p. 100-103° C.

(16alpha)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-16-(4-butynyl)estra-1,3,5(10)-trien-17-onedimethylhydrazone (36)

The alkylation of the steroid was performed with the anion generatedfirst of 4-bromo-1-butyne. The procedure was as follows. A solution of11.9 gr. of 35 in 100 ml of THF was treated at −20° C. with 20 ml of asolution of 1.5M BuLi in hexane. After stirring for 1 hr at −20° C. thereaction mixture was cooled to −70° C. A cold solution of the anion of4-bromo-1-butyne (prepared by addition of 36 ml of BuLi to 7.7 g of4-bromo-1-butyne in 50 ml of THF at −78° C.) was added dropwise and thereaction mixture was allowed to warm up to room temperature. The mixturewas then stirred for an additional 1 hr and then poured into 300 ml of10% aq. NH₄Cl. The product was extracted with ethyl acetate. Afterchromatography 9.5 g of 36 was obtained as an oil. R_(f) 0.85(toluene/ethylacetate 6/4).

(16alpha)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-16-(4-butynyl)estra-1,3,5(10)-trien-17-one(37)

To a solution of 9 g of 36 in 100 ml of THF and 70 ml of 1M acetatebuffer (pH 4,5) was added 15 g of periodic acid in 40 ml of ethanol. Themixture was stirred for 24 hr. Then 500 ml of water was added and theproduct was extracted with ethylacetate. Chromatography of the crudematerial thus obtained provided 4.2 g of 37.

(16alpha,17alpha)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-16,23-cyclo-19,24-dinorchola-1,3,5(10),20-tetraen-17-ol(38)

A solution of lithium naphtalenide was prepared from 3.4 g of naphtaleneand 150 mg of lithium chips in 30 ml of dry THF. This solution was addeddropwise to a solution of 560 mg of 37 in 5 ml of THF until a dark greencolor of the reaction mixture persisted. After stirring for anadditional 10 minutes the reaction mixture was poured into 30 ml ofNH4Cl and the product was extracted with ethyl acetate. Chromatographicpurification provided 150 mg of crystalline 38.

(16alpha,17alpha)-16,23-cyclo-19,24-dinorchola-1,3,5(10),20-tetraene-3,17-diol(39)

A solution of 130 mg of 35 in 5 ml of 5% HCl in methanol was stirred for2 hr at room temperature. The reaction mixture was then treated with 3ml of pyridine and concentrated and diluted with 10 ml of water. Theproduct was extracted in ethylacetate and finally purified bychromatography, to provide 65 mg of 39; M.p. 203-205° C.

EXAMPLE V

(7α,16α)-7-methyl-16-(prop-2-enyl)-estr-5(10)-ene-3,17-dione3,3-dimethylacetal (41)

A solution of lithium diisopropylamide was prepared from 16.6 ml of 1.5Mof butyllithium in hexane and 3.85 ml of diusopropylamine in 35 ml ofTHF at −20° C. After stirring for 20 min. a solution of 8.3 g of steroid40 in 30 ml of THF was added and the mixture was stirred for 20 minutesat −20°. Then after cooling to −40°, 2.2 ml of allylbromide was addedand then stirring was continued for an additional 4 hr at −20°, afterwhich period tlc monitoring showed completion of the reaction. Themixture was quenched by addition of 200 ml of 5% NaHCO₃ solution,followed by extraction with ethylacetate. Chromatography over silicagel(hexane-5% ethylacetate as eluent) provided 7.2 g of 41 as a whitesolid; M.p. 85-86°.

(7α,16α,17β)-7-methyl-16,17-bis(prop-2-enyl)-17-hydroxy-estr-5(10)ene-3-one3,3-dimethylacetal (42)

To a solution of 15 ml of 1 M allylmagnesium bromide in 30 ml of THF wasadded at −40° a solution of 4.5 g of 41 in 30 ml of THF. After stirringfor 30 min. at this temperature, the mixture was poured onto 250 ml of10% NH₄Cl solution and extracted with ethylacetate. The product thusobtained was chromatographed, to provide 3.2 g of the 16α,17α diallylderivative 42 as white amorphous material.

(7α,16α,17α)-7-methl-17-hydroxy-16,24-cyclo-19,21-dinorchola-5(10),22-dien-3-one3,3-dimethylacetal (43)

To a solution of 1.3 g of 42 in 30 ml of methylenedichloride was added200 mg of bis(tricyclohexylphosphine)benzylideneruthenium dichloride.The reaction was stirred until completion. The solvent was removedpartially by concentration and the residual material chromatographed ona silicagel column to provide 1.1 g of 43 as an amorphous whitematerial. R_(f)=0.38 (heptane/ethyl acetate 7/3 v/v).

(7α,16α,17α)-7-methyl-17-hydroxy-16,24-cyclo-19,21-dinorchola-4,22-dien-3-one(44)

A solution of 1 g of 43 in 30 ml of acetone was treated with 5 ml of 2NHCl. After stirring for 2 hr at room temperature the reaction wascomplete. After neutralization with 5% NaHCO₃ solution the mixture wasextracted with ethyl acetate and the product passed through a shortsilicagel column. The product thus obtained was treated withdiisopropylether, to provide 0.65 g of 44; M.p. 130-131; R_(f)(heptane/ethylacetate 7/3) 0.14.

EXAMPLE VI

(7α,16α,17α)-7-methyl-16-(prop-2-enyl)-17-hydroxy-pregna-5(10),20-dien-3-one3,3-dimethylacetal (45)

A solution of vinyllithium was prepared by addition of 0.8 ml of a 1.6Msolution of butyllithium in hexane to 0.32 ml of vinyltributyltin in 3ml of THF at −50° C. After stirring for 20 min. a solution of 300 mg of41 in 2 ml of THF was added dropwise. Upon stirring for an additional 15min. the mixture was quenched by addition of 20 ml of 10% NH₄Clsolution, followed by extraction of the product into ethylacetate.Subsequent chromatographic purification provided 120 mg of 45 as anamorphous material; R_(f) 0.56 (heptane/ethylacetate 7/3 v/v).

(7α,16β,17β)-16,17-dihydro-17-hydroxy-5′H-cyclopenta[16,17]estra-5(10),16-dien-3-one3,3-dimethylacetal (46)

To a solution of 120 mg of 45 in 4 ml of methylene dichloride was added30 mg of bis(tricyclohexylphosphine)benzylideneruthenium dichloride.After stirring for 2 hr the mixture was concentrated and filteredthrough a silica gel column, to provide 80 mg of 4.6 R_(f) 0.40(heptane/ethyl acetate 7/3 v/v).

(7α,16β,17β)-7-methyl-16,17-dihydro-17-hydroxy-5′H-cyclopenta[16,17]estra-4,16-dien-3-one(47)

A solution of 80 mg of 46 in 2 ml of acetone was treated with 0.2 ml of2N HCl. After stirring for 2 hr at room temperature the reaction mixturewas neutralized by addition of NaHCO₃, and diluted with water. Theproduct was extracted with ethylacetate and passed through a shortsilica column, to provide 45 mg of 47. Mp 175-176° C., R_(f) 0.49(heptane/ethylacetate 1/1 v/v).

EXAMPLE VII Test for Prevention of Ovariectomy-induced Bone Loss in Rats(anti-osteoporosis test) Introduction

Ovariectomy induces in rats bone loss, which is due to oestrogendeficiency. Administration of oestrogenic compounds prevents thiseffect. The test is used to evaluate a compound for anti-osteoporoticactivity in ovariectomised rats. The effect on bone mass can beevaluated by peripheral Quantitave Computed Tomography (pQCT)measurement of trabecular bone mineral density.

Test Animal

Mature virgin female Wistar rats preferentially, 225-250 g. Strain:Hsd/Cpd:Wu, SPF-bred by Harlan, CPB, Zeist, The Netherlands.

Experiment

On day 1 of the experiment the rats are weighed and distributed over thecages in order of body weight. The rat with the lowest body weight inthe first cage and the heaviest rat in the last cage. Treatments arerandomized over the rats per block. A block (group of 3+n treatments)consists of 1 Intact placebo rat, 1 OVX placebo rat, 1 OVX reference ratand 1 rat of each n treatments.

Sham-operation and ovariectomy are performed under ether anaesthesia.After recovery from the anaesthesia, within 24 h, vehicle, referencecompound or test compound is administered once or twice daily for 4weeks.

Bone mineral density measurement by pQCT

Trabecular bone mineral density (mg/cm³) of the metaphyseal part of thefemur was measured with a pQCT (peripheral Quantitative ComputedTomography machine; XCT 960A, Stratec, Birkenfeld, Germany) directlyafter autopsy on fresh tissue. Two 360° scans, which have, due to theX-ray beam, a standard thickness of 1 mm were taken. The scans have aresolution of 0.148×0.148 mm. One scan was taken at 5.5 mm from thedistal end of the femur, where trabecular bone mineral density of themetaphyseal part was measured. The other scan was taken in the diaphysisat 13.5 mm from the distal end, which contains no trabecular bone. Inthe latter scan cortical bone mineral density and the geometricalparameters, such as cortical thickness, total bone area, outer and innerdiameter, were determined. Intra- and inter-assay variation for themeasurement of trabecular bone mineral density in the distal femur wereabout 2-3%. The XCT-960A was calibrated with a standard ofhydroxyapatite embedded in acrylic plastic.

Interpretation of Results

Ovariectomy causes a statistically significant decrease in trabecularbone mineral density (P≦0.05, 2 way ANOVA). Test compounds areconsidered to be active when mean bone mineral density values of thedistal femur are significantly increased as compared to theovariectomised control group.

The active dose (ED₅₀) is the dose where a mean proportional differencein trabecular bone mineral density between 40 and 60% is reached ascompared to the sham and ovariectomised group.

References

Wronski T. J. and Yen C. F.: The ovariectomised rat as an animal modelfor postmenopausal bone loss. Cells and Materials, Supp. 1 (1991):69-76.

Yamazaki I. and Yamaguchi H.: Characteristics of an ovariectomisedosteopenic rat model. J. Bone Min. Res. 4 (1989): 12-22.

Ederveen A. G. H., Spanjers C. P. M., Quaijtaal J. H. M. andKloosterboer H. J.: Effect of treatment with tibolone (Org OD 14) or17α-ethinyl estradiol on bone mass, bone turnover and biomechanicalquality of cortical and trabecular bone in mature ovariectomised rats.Osteoporosis Int. in press, 1998.

EXAMPLE VIII Test for Receptor-binding In vitro

The relative progesterone receptor binding affinity of the compounds ofthe invention was measured for cytoplasmic progesterone receptorspresent in human breast tumor cells (MCF-7 cells, incubation time 16 h.,temperature 4° C.) and compared with the affinity of(16α)-16-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione (according to theprocedure described by E. W. Bergink et al., J. Steroid Biochem., Vol.19, 1563-1570 (1983)). The relative estradiol receptor binding affinitywas measured in the same manner as described above but using17βestradiol as a reference.

Test for Estrogenic Activity In vivo

The in vivo estrogenic activity was determined by means of the wellknown Allen Doisy test, described in F. Allen, L. A. Doisy, J. Amer.Med. Assoc., 81,819-821 (1923).

Test for Proyestaienic Activity In vivo

The in vivo progestagenic activity was determined by means of the wellknown McPhail test, described in McPhail, M. K.: The assay of progestin,Journal of Physiology, 1934, 83:145-156.

Several of the compounds according to the Examples I-VI, as well asother compounds according to the invention synthesized in analogousmanner, were subjected to the tests described in the Examples VII andVIII. The results are described in the Table, in which the type ofA-ring and the substitution at carbon atoms nos. 7, 11, and 17 isindicated. In the columns captioned E and P, the relative bindingaffinities for the estrogen and progesterone receptors are given; theED₅₀ results of the AllenDoisy and the McPhail tests have been indicatedin μg/kg. In the column captioned “Osteoporosis”, the ED₅₀ results ofthe anti-osteoporosis test are given (dose in μg/kg, day, as describedabove).

Table Representing The Relative Binding Affinities To The HumanEstradiol (E) Or Progesterone (P) Receptor And The In Vivo HormonalActivities (ED₅₀) Upon Oral Administration E P AllenDoisy McPhailOsteoporosis A-ring 7α 11β 16α,17α Code (%) (%) (μg/kg) (μg/kg) (μg/kg,day) Δ4 = 5 H H 5-ring + 4′S-methyl 38541 58 >500 125 >1000 Δ4 = 5 H H5-ring + 4′S propyl 37977 151 >4000 500 >1000 Δ4 = 5 H H 6-ring 37518115 >4000 125 >2000 Δ4 = 5 H methyl 5-ring + 4′R-butyl 38276 115 >500125 >1000 Δ4 = 5 H methyl 5 ring + 4′S azidomethyl 38322 44 >50063 >1000 Δ4 = 5 H ethyl 6-ring 37943 96 192 1000 400 Δ4 = 5 H ethyl 5ring + 4′S-ethyl 38610 0.3 32 >125 125 Δ4 = 5 H ethyl 5-ring +4′S-propyl 38577 139 192 >500 250 Δ4 = 5 methyl H 5-ring 37352 36 1000250 500 Δ4 = 5 propyl H 5-ring + 4′R methyl 38550 36 125 >125 125 Δ4 = 5methyl H 5-ring + 4″S methyl 38049 250 >2000 1000 >1000 Δ5 = 10 methyl H5-ring 37351 4 4000 2000 1000 Δ5 = 10 H ethyl 5-ring + 4′R propyl 381518 125 >1000 ND Δ5 = 10 H H 6-ring 37516 13 >4000 1000 >2000 aromatic H H6-ring 37469 1 23 >4000 >2000 >4000 aromatic H H 5-ring + 4′R-propyl37968 1 6 >1000 >4000 ND aromatic H H 5-ring + 4′S-propyl 37969 325 >1000 4000 >1000 aromatic H ethyl 6-ring 37862 96 2 32 ND <16aromatic methyl H 5-ring + 4′S-methyl 37893 38 11 500 >4000 500 aromaticmethyl H β 5-ring + 4′S-propyl 38079 <1 1 >4000 ND ND aromatic methyl H6-ring 37828 11 10 192 — 500 aromatic propyl H 5-ring + 4′R-methyl 3851411 4 24 >2000 <32 aromatic propyl H 5-ring + 4′S-methyl 38481 23 664 >4000 125 aromatic propyl H 6-ring 38515 16 10 96 4000 190 aromaticpropyl H β 5-ring + 4′R-methyl 38513 0.2 — 2000 >125 ND NC NotCompetitive; ND Not Determined;

What is claimed is:
 1. A steroid compound having the formula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; E represents, together with carbon atoms 16and 17 of ring D, a four to seven-membered ring, said ring being α withrespect to the D-ring, substituted with R_(E) and optionally comprisingone or two endocyclic double bonds; R_(E) is H; C₁₋₆-alkyl;C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene; C₂₋₆-spiro-anellatedcycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, wherein R′ (andin the case of R_(E) being —NR′R′ each R′ independently of the other) isan alkyl with 1 to 6 carbon atoms; —NCO; —(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN,with n is 0 to 5, wherein the alkyl, alkenyl, alkynyl, alkylidene orcycloalkyl group may be substituted with 1 to 3 substituentsindependently selected from the group consisting of —OR′; —SR′; —OOCR′;—NHR′; —NR′R′; —NHCOR′, with R′ being defined as above; fluorine atomsand chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or —OOCR wherein R is analkyl with 1 to 6 carbon atoms; wherein the steroid compound optionallymay have one or more double bonds chosen from the group of Δ9(10);Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of the rings A or B may bearomatic.
 2. A steroid compound according to claim 1, wherein the E-ringis a six-membered ring.
 3. A steroid compound according to claim 1,wherein R₇ is α-propyl, the E-ring is a six-membered ring, R₃ and R₁₇are OH, and R₆, R₁₁, and R_(E) are H.
 4. A steroid compound having theformula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of the rings Aor B may be aromatic.
 5. A steroid compound according to claim 4,wherein the E-ring is a six-membered ring.
 6. A steroid compoundaccording to claim 4, wherein R₇ is α-propyl, the E-ring is asix-membered ring, R₃ and R₁₇ are OH, and R₆, R₁₁, and R_(E) are H.
 7. Apharmaceutical composition comprising the steroid compound according toany one of claims 1 to 6, and a pharmaceutically acceptable auxiliary.8. A method for treating or preventing peri-menopausal orpost-menopausal complaints, comprising administering to a person in needthereof an effective amount of a steroid compound having the formula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic.
 9. A method of contraception, comprisingadministering to a subject in need thereof a contraceptive amount of asteroid compound having the formula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic.
 10. A method for treating or preventingosteoporosis, comprising administering to a person in need thereof aneffective amount of a steroid compound having the formula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic.
 11. A method for providing an estrogenicand/or progestagenic effect, comprising administering to a subject inneed thereof an effective amount of a steroid compound having theformula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic.
 12. A method for stimulating estrogenand/or progesterone receptors in a subject, comprising administering tothe subject in need thereof an effective amount of a steroid having theformula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic.
 13. A process for the preparation of 16,17anellated steroid compound having the formula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic, comprising the steps of taking a 17-ketosteroid having the formula:

wherein the substituent groups have the meaning above, and attaching, oncarbon atom 16, adjacent to the 17-keto moiety, an alkyl chain,substituted or not, suitably functionalized so as to obtain anω-iodoalkyl moiety, and bringing about the ring-closure of theω-iodoalkyl moiety by treatment with an organometallic reagent.
 14. Aprocess for the preparation of a 16,17 anellated steroid compound havingthe formula

wherein R₃ is ═O; —OH; ═NOR; —OR or OOCR, in which R is an alkyl grouphaving 1 to 6 carbon atoms; R₆ is H; ═CH₂ or —(CH₂)_(m)H with m is 1 or2; R₇ is H; C₁₋₄-alkyl; C₂₋₅-alkenyl or C₂₋₅-alkynyl, wherein the alkyl,alkenyl or alkynyl group may be substituted with 1 to 3 halogen atomsindependently selected from the group consisting of fluorine andchlorine atoms; R₁₁ is H; C₁₋₄-alkyl; C₂₋₄-alkenyl; C₂₋₄-alkynyl orC₁₋₄-alkylidene, wherein the alkyl, alkenyl, alkynyl or alkylidene groupmay be substituted with 1 to 3 halogen atoms independently selected fromthe group consisting of fluorine and chlorine atoms; E represents,together with carbon atoms 16 and 17 of ring D, a four to seven-memberedring, said ring being α with respect to the D-ring, substituted withR_(E) and optionally comprising one or two endocyclic double bonds;R_(E) is H; C₁₋₆-alkyl; C₂₋₆-alkenyl; C₂₋₆-alkynyl; C₁₋₆-alkylidene;C₂₋₆-spiro-anellated cycloalkyl; —OR′; —SR′; —OOCR′; —NHR′; —NR′R′;—NHCOR′, wherein R′ (and in the case of R_(E) being —NR′R′ each R′independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO;—(CH₂)_(n)—N₃ or —(CH₂)_(n)—CN, with n is 0 to 5, wherein the alkyl,alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with1 to 3 substituents independently selected from the group consisting of—OR′; —SR′; —OOCR′; —NHR′; —NR′R′; —NHCOR′, with R′ being defined asabove; fluorine atoms and chlorine atoms; R₁₇ is —OH; —OCH₂OR; —OR or—OOCR wherein R is an alkyl with 1 to 6 carbon atoms; wherein thesteroid compound optionally may have one or more double bonds chosenfrom the group of Δ9(10); Δ5(10); Δ4(5); Δ11(12); Δ14(15); or any of therings A or B may be aromatic, comprising taking a 17-keto steroid havingthe formula:

wherein the substituent groups have the meaning above and attaching, oneach of the carbon atoms 16 and 17, an alkenyl chain substituted or not,and bringing about the ring-closure via olefin metathesis, using acatalyst derived from a transition metal.